Neuroprotection by Transgenic Expression of Glucose-6-Phosphate Dehydrogenase in Dopaminergic Nigrostriatal Neurons of Mice

Mejı́as, Rebeca; Villadiego, Javier; Pintado, Cristina; Vime, Pablo J.; Gao, Lin; Toledo‐Aral, Juan José; Echevarría, Miriam; López‐Barneo, José

doi:10.1523/jneurosci.0122-06.2006

Cited by 60 publications

(50 citation statements)

References 59 publications

(84 reference statements)

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“…42 As with our results, these findings provided evidence that G6PD function has protective potential in the brain. Further gene expression studies in these G6PD-overexpressing mice displayed changes mainly in the expression of proteins related to antioxidant defense, detoxification, and synaptic function.…”

Section: Acs Chemical Neurosciencesupporting

confidence: 91%

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Jeng

Loniewska

Wells

2013

ACS Chem. Neurosci.

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Glucose-6-phosphate dehydrogenase (G6PD) protects the embryo from endogenous and xenobiotic-enhanced oxidative DNA damage and embryopathies. Here we show in aged mice that G6PD similarly protects against endogenous reactive oxygen species (ROS)-mediated neurodegeneration. In G6PD-normal (G6PD +/+ ) and heterozygous (G6PD +/def ) and homozygous (G6PD def/def ) G6PD-deficient male and female mice at about 2 years of age, oxidative DNA damage in various brain regions was assessed by 8-oxo-2′-deoxyguanosine formation using high-performance liquid chromatography and immunohistochemistry. Morphological changes in brain sections were assessed by H&E staining. DNA oxidation was increased in G6PD def/def mice in the cortex (p < 0.02), hippocampus (p < 0.01) and cerebellum (p < 0.006) compared to G6PD +/+ mice, and was localized to distinct cell types. Histologically, in G6PD +/def mice, enhanced regionally and cellularly specific neurodegenerative changes were observed in those brain regions exhibiting elevated DNA oxidation, with a 53% reduction in the Purkinje cell count. These results show G6PD is important in protecting against the neurodegenerative effects of endogenous ROS in aging, and suggest that common hereditary G6PD deficiencies may constitute a risk factor for some neurodegenerative diseases.

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Section: Acs Chemical Neurosciencesupporting

confidence: 91%

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Jeng

Loniewska

Wells

2013

ACS Chem. Neurosci.

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“…Intracellular glutathione, with the help of nitric oxide (17), also maintains cytochrome c in a reduced and inactive state, thus inhibiting cytochrome c-induced apoptosis in neurons (18). The protective role of the brain PPP against ROS and apoptosis has been demonstrated in transgenic mice with increased expression of G6PDH when challenged with oxidative stress (66). Also, up-regulation of the PPP is a distinctive feature of surviving brain cells from individuals with DAT (67)(68)(69).…”

Section: Discussionmentioning

confidence: 99%

Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition

Vlassenko¹,

Vaishnavi²,

Couture³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

352

303

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Amyloid-β (Aβ) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Aβ plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Aβ deposition in individuals with DAT and cognitively normal participants with elevated Aβ, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology.Alzheimer's disease | default mode network | positron emission tomography C erebral amyloid-β (Aβ) plaque deposition is a hallmark of Alzheimer's disease (AD) (1, 2), and there is clinical pathological evidence that Aβ deposition may precede clinical manifestation of cognitive deficits and dementia of the Alzheimer type (DAT) (3, 4). However, it is unclear whether the site and extent of Aβ deposition is related to any preceding pattern of brain activity or metabolism.A radiotracer with high affinity to Aβ plaques, N-methyl-[ 11 C] 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or 11 C-PIB, for "Pittsburgh Compound-B"), has been developed for PET study and has demonstrated substantially increased regional uptake in individuals with DAT and also in some cognitively normal older persons (5-7). The spatial distribution of Aβ plaques by PET imaging in individuals with DAT appears strikingly similar to the default mode network (DMN), a group of brain regions that are more active when normal individuals are not engaged in attentiondemanding, goal-directed task performance (8-10).The unique distribution of Aβ in DAT suggests that something unique to these brain areas predisposes them to the pathophysiology of AD (9, 11). One of the many features of these areas is their reliance on glucose outside its usual role as substrate for oxidative phosphorylation (12). In adequately oxygenated tissue, this use of glucose usually is referred to as "aerobic glycolysis" and accounts for 10-15% of the glucose metabolized by the brain (13-15). It should be noted that the term "aerobic glycolysis" includes glycolysis itself (metabolism of glucose-6-phosphate to pyruvate) as well as glucose entering the pentose phosphate shunt and glycogen synthesis.Because many critical functions are associated with glucose outside its traditional role in supplying energy through oxidative phosphorylation (16)(17)(18)(19), this relationship might signal a causal element in the chain of events leading to DAT. As a first step in exploring this possibility, we wanted to confirm the apparent spatial relationship between DAT and those brai...

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“…Histological analyses and stereological cell counts were done by following previously described protocols (23,32,38). In brief, mice were anesthetized and killed by decapitation.…”

Section: Methodsmentioning

confidence: 99%

Differential Impairment of Catecholaminergic Cell Maturation and Survival by Genetic Mitochondrial Complex II Dysfunction

Díaz-Castro

Pintado

García-Flores

et al. 2012

Molecular and Cellular Biology

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The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a "floxed" SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson's disease. Unexpectedly, TH ؉ neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period.

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Neuroprotection by Transgenic Expression of Glucose-6-Phosphate Dehydrogenase in Dopaminergic Nigrostriatal Neurons of Mice

Cited by 60 publications

References 59 publications

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition

Differential Impairment of Catecholaminergic Cell Maturation and Survival by Genetic Mitochondrial Complex II Dysfunction

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